Left Atrial Appendage Closure in Atrial Fibrillation to Prevent Stroke Matthew J. Price MD Director, Cardiac Catheterization Laboratory Scripps Clinic La Jolla, CA, USA price.matthew@scrippshealth.org
Risk Factors for Stroke From The Perspective of the 17 th -Century Physician To this variety of apoplexy those are most liable who lead an idle life, who are obese, whose face and hands are constantly livid and whose pulse constantly unequal. Historiae Apoplecticorum Johann Jakob Wepfer, 1658 Apoplexy: Incapacity resulting from a cerebral hemorrhage or stroke.
Prevalence of Antithrombotic Therapies in AF Patients Across the Spectrum of Stroke Risk: Data from the NCDR-PINNACLE Registry N=429,417 <50% of highrisk patients get OACs Hsu JC et al, JAMA Cardiol. 2016;1(1):55-6262
Effect of NOACs on Utilization of OAC in Indicated Population: Data from the NCDR- PINNACLE Registry N=655,000 CHA 2 DS 2 VASC 2 Marzec LN et al, JACC 2017; 69(20): 2475-24842484
OACs are Frequently Discontinued 30% 50% Martinez et al, Thromb Haemost 2015
The Non-Vitamin K Oral Anticoagulants (NOACs): Clinical Trial Summary Drug RE-LY Dabigatran 150mg/d ROCKET-AF Rivoraxaban 20mg/day ARISTOTLE Apixaban 5mg bid ENGAGE-AFAF Edoxaban 60mg/day CHADS 2 2.2 3.5 2.1 2.8 TTR, control 67% 58% 66% 68% Ischemic stroke 0.76 (0.60-0.98) 0.94 (0.75-1.17) 0.92 (0.74-1.14) 1.00 (0.83-1.19) Hemorrhagic 0.26 (0.14-0.59 (0.37-0.51 (0.34-0.54 (0.38- stroke 0.49) 0.93) 0.75) 0.77) All-cause 0.88 (0.77-0.85 (0.70-0.89 (0.80-0.92 (0.83- mortality 1.00) 1.02) 0.998) 1.01) Major bleed 0.93 (0.81-1.07) 1.04 (0.90-1.20) 0.69 (0.60-0.80) 0.80 (0.71-0.91) GI bleeding 1.50 (1.19-1.39 (1.19-0.89 (0.70-1.23 (1.02-1.89) 1.61) 1.15) 1.50)
The Bad Actor: The Left Atrial Appendage Why not a local therapy for a local problem? >90% of stroke-causing thrombus originates in the LAA Thromboembolic stroke from AF more debilitating due to size of clots Blackshear J.L. Odell J.A., Annals of Thoracic Surgery, 1996;61:755-759
A Local Approach to Stroke Prevention in AF is Not A Novel Idea
LAA Occluders Clinically Available (CE Mark or FDA-approved) or Currently Under Investigation U.S.: : Watchman (FDA approved), Amulet (RCT), Wavecrest (RCT soon) OUS: WATCHMAN Amplatzer Amulet LifeTech Occlutech Prolipsis Cardia Acroredis
WATCHMAN LAA Occluder Catheter-based Delivery Available sizes: 21, 24, 27, 30, 33 mm diameter Nitinol Frame 10 active fixation anchors - designed to engage tissue for stability Proximal Face 160 micron membrane PET cap designed to block emboli and promote healing Repositionable & retreivable
Watchman LAA Closure at 1 Year FU
WATCHMAN: FDA Indications for Use The WATCHMAN is indicated to reduce the risk of thromboembolism from the LAA in patients with AF who: Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2VASc scores and are recommended for anticoagulation Are deemed by their physicians to be suitable for warfarin; and Have an appropriate rationale to seek a nonnonpharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared with warfarin.
Prospective U.S. Dataset for WATCHMAN LAA Closure in Warfarin-Eligible Patients Key Trials N Design PROTECT AF (2005-2008) 707 Prospective RCT - 2:1, non-inferiority trial of LAA closure vs. warfarin. CAP (2008-2010) 566 Prospective continuing access registry to gain further information prior to PMA approval. PREVAIL Prospective RCT - 2:1, non-inferiority trial to collect 407 (2010-2012) additional information on the WATCHMAN Device. CAP2 (2012-2014) 579 Prospective continuing access registry prior to PMA approval. Total patients >2,000 ~7,000 Patient-Years of Follow-up Reddy, et al. JAMA. 2014 ;312(19): 1988-1998 1998 Reddy VY et al. Circulation. 2011; 123:417-424424 Holmes, Kar, Price MJ et al., JACC 2014,4(1): 1-11 11
Post-procedural Adjunctive PostPharmacotherapy in the WATCHMAN Clinical Trials Price MJ et al, JACC Cardiovasc Interv 2015; 8:1925 8:1925--32 32..
Patient-Level PROTECT AF/PREVAIL Meta PatientMeta-Analysis at 5 Years: WATCHMAN LAAC Compared With Warfarin HR p-value 0.82 0.3 0.96 0.9 Ischemic stroke or SE 1.7 0.08 Hemorrhagic stroke 0.2 0.0022 Ischemic stroke or SE >7 days 1.4 0.3 0.59 0.03 All-cause death 0.73 0.04 Major bleed, all 0.91 0.6 Major bleeding, non procedure-related 0.48 0.0003 Efficacy All stroke or SE CV/unexplained death Favors WATCHMAN 0.01 Reddy et al, JACC 2017 0.1 Favors warfarin 1 Hazard Ratio (95% CI) 10
Patient-Level PROTECT AF/PREVAIL Meta PatientMeta-Analysis at 5 Years: WATCHMAN LAAC Compared With Warfarin HR p-value 0.82 0.3 0.96 0.9 Ischemic stroke or SE 1.7 0.08 Hemorrhagic stroke 0.2 0.0022 Ischemic stroke or SE >7 days 1.4 0.3 0.59 0.03 All-cause death 0.73 0.04 Major bleed, all 0.91 0.6 Major bleeding, non procedure-related 0.48 0.0003 Efficacy All stroke or SE CV/unexplained death Favors WATCHMAN 0.01 Reddy et al, JACC 2017 0.1 Favors warfarin 1 Hazard Ratio (95% CI) 10
Patient-Level PROTECT AF/PREVAIL Meta PatientMeta-Analysis at 5 Years: WATCHMAN LAAC Compared With Warfarin HR p-value 0.82 0.3 0.96 0.9 Ischemic stroke or SE 1.7 0.08 Hemorrhagic stroke 0.2 0.0022 Ischemic stroke or SE >7 days 1.4 0.3 0.59 0.03 All-cause death 0.73 0.04 Major bleed, all 0.91 0.6 Major bleeding, non procedure-related 0.48 0.0003 Efficacy All stroke or SE CV/unexplained death Favors WATCHMAN 0.01 Reddy et al, JACC 2017 0.1 Favors warfarin 1 Hazard Ratio (95% CI) 10
PREVAIL: Rates of the Component Endpoints PREVAIL Subjects Device (n=269) No. of Events Control (n=138) Rate * No. of Events Rate * p-value 2:1 Randomization Primary Efficacy: Stroke/SE/CV Death 37 / 1038.3 3.65 15 / 530.4 2.94 0.47 All Stroke 19 / 1042.4 1.97 7 / 530.4 1.29 0.32 17 / 1043.1 1.68 4 / 533.3 0.73 0.13 2 / 1084.6 0.18 3 / 538.0 0.54 0.23 1 / 1080.6 0.09 0 / 540.9 n/a n/a 18 / 1084.7 1.79 10 / 540.9 1.98 0.76 Ischemic Stroke Hemorrhagic Stroke Systemic Embolism CV/Unexplained Death Yearly stroke rate of 0.73 on warfarin in a population CHA2DS2VASc = 4.1 ±1.2! Wide confidence intervals, small # of patients
Comparative Stroke Rates Between WATCHMAN LAAC and Untreated AF 10 Untreated AF Treated with Warfarin WATCHMAN Arm 8 Ischemic Stroke Risk (events per 100 pt-yrs) 6 4 2 PROTECT AF 1.3 PREVAIL 1.7 WASP 1.5 CAP 1.2 CAP2 2.3 EWOLUTION 1.1 0 1 2 3 4 5
Patient-Level Meta PatientMeta--Analysis: WATCHMAN Associated With Superior Reduction in Disabling Strokes 2.00% Disabling/Fatal Strokes Non-Disabling Strokes 1.50% 55% Reduction 1.00% 0.50% HR 0.45 (0.21 0.94) P=0.03 0.00% WATCHMAN warfarin Disabling Stroke defined as MRS 2
100 90 WATCHMAN Warfarin Free of Major 80 Bleeding Event 70 (%) HR 0.28 [95% CI, 0.23 to 0.35] 72% 60 Relative Reduction In Major Bleeding WATCHMAN Arm Warfarin +Aspirin 50 0 Warfarin +Aspirin 7 8 45 46 Price MJ et al, JACC Cardiovasc Interv 2015; 8:1925 8:1925--32 32.. Plavix +Aspirin Aspirin 180 6 60
EWOLUTION Registry: Serious Procedure/Device Related Events With Watchman LAA Closure Through 7 Days N=1021 Boersma LV, et al. Eur Heart J. J. 2016.
Outcomes in the WATCHMAN PostPostApproval Experience: N=3822 Post-FDA Approval Experience Complications Pericardial Tamponade Treated with Pericardiocentesis Treated Surgically 39 (1.02%) 24 (0.63%) 12 (0.31%) Resulted in Death Pericardial Effusion No Intervention 3 (0.078%) 11 (0.29%) Procedure-Related Stroke 3 (0.078%) 9 (0.24%) Device Embolization Removed Percutaneously 3 Removed Surgically 6 Death Procedure-Related Mortality Additional Mortality within 7 days Holmes DR, JACC 2017 3 (0.078%) 1 (0.026%)
ASAP-TOO Study Design Prospective, randomized, multi-center, global Patients with non-valvular atrial fibrillation deemed not suitable for oral anti-coagulation therapy to reduce the risk of stroke. Randomized 2:1 (Watchman vs Control) Considering Group Sequential Design Allows early looks; potential to stop early for benefit 888 subjects at up to 100 global sites Follow-Up* 45 Day with TEE 6,18 month phone visit 12 month with TEE Years 2-5 bi-annually * Brain imaging required at baseline if prior stroke or TIA 2012 MFMER slide-29
Watch-TAVR Severe AS and Atrial Fibrillation N=400 Randomization 1:1 TAVR + Watchman TAVR + Medical management Primary endpoint Death, Stroke and Major Bleeding Investigator initiated, Co-PI Samir Kapadia, Martin Leon Sponsored by BSc Cleveland Clinic
Decision Making Scheme for Stroke Prevention Therapy in AF AF patient at high thromboembolic risk by CHA2DS2VASC score Low bleeding risk, compliant, can afford therapy NOAC (or VKA) Not good candidate for long-term OAC (prior bleed, bleeding risk, on APT, noncompliant, poor VKA candidate & can t afford/take NOAC) but can tolerate short-term therapy Commercial Watchman Absolute or strong contraindication to even short-term OAC ASAP-TOO (WM vs no therapy) Amulet vs. Watchman RCT
The True Measure of Success Just finished FU TEE, told to discontinue warfarin Bruising from warfarin
1 Week Later: Husband Can D/C Warfarin Time Warfarin Time for a Dinner Date With Lots of Leafy Greens!!!
LAA Closure, TAVR, ASD/PFO, Mitral Repair, and More Featuring live case demonstrations, hands-on workshopsand additional satellite symposia! A Pract ical Approach February 7-9, 2018 San Diego Marriott La Jolla La Jolla, California Overview Course Directors Scripps Health s Structural Heart Intervention and Imaging conference is designed to provide a practical, cutting-edge, case-based assessment of the emerging area of structural heart disease intervention and interventional cardiovascular imaging. The expert faculty will include interventionalists, invasive cardiologists, and echocardiographers. Faculty will discuss patient selection, pre-procedural assessment, procedural tips, techniques and challenges (including concurrent imaging) during the performance of the procedures, and conclude with assessment of outcomes and future directions. M atthew J. Price, M D, FACC Director, Cardiac Catheterization Laboratory Scripps Clinic/Green Hospital Assistant Professor Scripps Translational Science Institute La Jolla, Califor nia David S. Rubenson, M D, FACC, FASE Director, Cardiac Non-Invasive Laboratory Scripps Clinic La Jolla, Califor nia Contact Us Scripps Conference Services & CME 11025 North Torrey Pines Road, Ste. 200 La Jolla, California 92037 P: 858-652-5400 E: med.edu@scrippshealth.org W: www.scripps.org/conferenceservices